Microarray Studies on 211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Nonthyroid Tissues

Targeted alpha-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation, resulting in a certain percentage of free radio-nuclide in the body. The radiohalogen At-211 accumulates in various tissues, with specifically high uptake in the thyroid. When normal thyroid function is disturbed because of ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiologic function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from At-211. Here, we present supportive evidence on systemic effects after At-211 administration. Methods: Expression microarray data from the kidney cortex and medulla, liver, lungs, and spleen were used from previous studies in which mice were intravenously injected with 0.064-42 kBq of At-211 and killed after 24 h or injected with 1.7 kBq of At-211 and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software. Results: Responses in IR- or TH-associated gene signatures were tissue specific and varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least an extent similar to the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream regulators with differences in incidence and strength of regulation depending on tissue type. Conclusion: These findings indicate that transcriptional regulation in various nonthyroid tissues was-in part-induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures.